8C8W

Priestia megaterium mupirocin hyper-resistant HIGH motif mutant of type 2 isoleucyl-tRNA synthetase complexed with an isoleucyl-adenylate analogue

Summary for 8C8W

• Entry DOI: 10.2210/pdb8c8w/pdb
• Descriptor: Isoleucine--tRNA ligase, N-[ISOLEUCINYL]-N'-[ADENOSYL]-DIAMINOSUFONE, D(-)-TARTARIC ACID, ... (5 entities in total)
• Functional Keywords: antibiotic, mupirocin-resistant, ilers2, rna-binding protein, c-terminal domain, rna binding protein
• Biological source: Priestia megaterium
• Total number of polymer chains: 1
• Total formula weight: 119053.50

Authors

Brkic, A.,Leibundgut, M.,Jablonska, J.,Zanki, V.,Car, Z.,Petrovic Perokovic, V.,Ban, N.,Gruic-Sovulj, I. (deposition date: 2023-01-21, release date: 2023-08-16, Last modification date: 2024-03-27)

Primary citation

Brkic, A.,Leibundgut, M.,Jablonska, J.,Zanki, V.,Car, Z.,Petrovic Perokovic, V.,Marsavelski, A.,Ban, N.,Gruic-Sovulj, I.
Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.
Nat Commun, 14:5498-5498, 2023

PubMed Abstract: Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 10-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance.

PubMed: 37679387
DOI: 10.1038/s41467-023-41244-3

Experimental method

X-RAY DIFFRACTION (2.29 Å)